EP0261429A1 - Penetration enhancement systems and the preparation thereof - Google Patents
Penetration enhancement systems and the preparation thereof Download PDFInfo
- Publication number
- EP0261429A1 EP0261429A1 EP87112412A EP87112412A EP0261429A1 EP 0261429 A1 EP0261429 A1 EP 0261429A1 EP 87112412 A EP87112412 A EP 87112412A EP 87112412 A EP87112412 A EP 87112412A EP 0261429 A1 EP0261429 A1 EP 0261429A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- fatty
- procaterol
- drugs
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Definitions
- transdermal administration of drugs offers a viable alternative to oral dosage forms.
- transdermal delivery systems are not always efficacious due to such factors as the failure of the drug to sufficiently penetrate the cutaneous membrane and enter the body to produce therapeutic systemic effects.
- enhancers are generally thought of as solvents for the drug or drugs being used, but it is more accurate to term them penetration enhancers since--via a mechanism which is not clearly understood--they assist in the movement of an active ingredient across a living membrane, eg., the skin, and into the body fluid, eg., the blood stream.
- the systems which enhance transmembranal penetration are generally combinations of fatty acids and/or their esters.
- the invention relates to compositions and methods for the administration of bioaffecting agents, eg., drugs, via living membranes, eg., skin, via topical application; ie., by contacting the compositions with the living membranes.
- bioaffecting agents eg., drugs
- 0.5-3 wt. % procaterol is combined with 2-90 wt. % linoleic acid and 10-98% propylene glycol to produce compositions useful for transdermal administration.
- compositions and methods of the invention have several advantages over the prior art delivery systems. Since the instant system permits delivery via buccal, rectal, mucosal, nasal and dermal membranes, the drug can enter the bloodstream without entering the gastrointestinal tract. Transmembranal dosage forms generally do not produce the side effects, such as nausea and the like, which are often associated with the oral administration of drugs.
- compositions need not be administered via injection, the unpleasantness of that type of delivery is avoided.
- Weight percentages are based on total composition weight unless staged otherwise.
- bioaffecting agents which can be employed in the compositions of the invention include a wide range of known drug and beneficial substances and/or derivatives thereof.
- derivatives thereof is meant pharmaceutically acceptable derivatives of the bioaffecting base, or drug agent, as well as prodrugs and metablites.
- procaterol useful derivatives would include procaterol salts, with the hydrochloride salt being exemplary.
- Other useful forms of procaterol include procaterol base, procaterol sulfate and the like.
- compositions containing a drug in combination with one or more other drugs are contemplated.
- organic and inorganic salts thereof can be used.
- the nature of the salt is not essential as long as the drug or other agent maintains its value as a medicament and is compatible with the penetration enhancer(s) or other vehicle(s) employed.
- Exemplary acid salts include hydrochloride, hydrobromide, orthophosphate , benzoate, maleate, tartarate, succinate, citrate, salicylate, sulfate, acetate, and the like.
- Useful bioaffecting agents include; Antihistamines, such as chlorpheniramine maleate, phenimadamine tartarate, pyrilamine maleate, doxylamine succinate, and phenyltolomaxine citrate; Decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine; Various alkaloids, such as codeine phosphate, codeine sulfate and morphine; Laxatives, vitamins and antacids; Anticholesterolemic and antilipid agents; Antiarrhythmics such as N-acetylprocainamide; Antipyretics and analgesics such as acetaminophen, aspirin, and ibuprofen; Appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; and Expectorants such as guaifenesin.
- Additional useful active medicaments include anti-inflammatory substances, coronary dilators, cerebral dilators, vasodilators, anti-infectives, psychotropics, antimanics, stimulants, laxatives, decongestants, gastro-intestinal sedatives, antidiarrheal preparations, antianginal drugs, vasodilators, antihypertensive drugs, vasoconstrictors and migraine treatments, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants and antithrombotic drugs, hypnotics, sedatives, antiemetics, antinauseants, anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs
- Preferred drugs for use in the instant compositions and methods are; procaterol, 4,5-dihydro-6-[4-(IH-imidozole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone morphine, hydromorphone, propranolol, chlorpheniramine and derivatives thereof.
- Procaterol, the pyridazinone, propranolol and their derivatives are most preferred.
- the daily dosages for human use of these preferred drugs are believed to be about 200 mg/day for procaterol and about 2 mg/day. for 45-dihydro-6-[4-(1H-imidazole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone ("the pyridazinone") and higher for propranolol.
- the penetration enhancer systems of the invention contain at least one fatty compound in combination with a non-fatty hydroxyl compound.
- fatty compounds mean compounds related to, or existing as, any of the saturated or unsaturated monocarboxylic acids that occur naturally in the form of glycerides in fats and fatty oils.
- the fatty compounds which can be employed are essential fatty acids, their esters, alcohols and other related compounds.
- Useful fatty components of the instant enhancement systems include saturated and unsaturated aliphatic compounds. Generally the unsaturated compounds contain about 8 to 24 carbon atoms.
- Fatty acids, alcohols and esters to be employed herein include those containing oleic, linoleic, linoleic, moieties and the like. Mixtures are comtemplated.
- the preferred group of fatty components include linoleic acid (ie., 9,12- octadienoic acid) and related compounds.
- Suitable esters of this or other fatty acid(s) to be employed include the C 1-3 esters eg., the methyl, ethyl, and propyl esters, and the like.
- an alcoholic fatty component When an alcoholic fatty component is employed, it is generally preferred that it contain no more than one hydroxyl group, ie., monohydroxy alcoholic fatty compounds are preferred.
- One such compound is linoleyl alcohol.
- the other, or secondary, component of the penetrant system of the invention is not a fatty substance.
- this other component is a solvent for the bioaffecting agent.
- Useful solvents are generally mono-or polyhydroxyl-containing compounds which may, optionally, contain ester groups.
- Hydroxyl compounds to be used as the secondary component include compounds containing one or more hydroxyl groups. Polyols are preferred. Polyols containing one to four carbon atoms are more preferred. Propylene glycol, polyethylene glycols (eg., PEG 400) and tetraglycols are highly preferred. Isopropanol is also useful. Mixtures are operable.
- the ester group-containing compound useful in the secondary component of the penetration enhancer system will be at least one compound which contains one or more ester groups.
- Compounds containing 6 to 30 carbon atoms and three or more ester groups are preferred.
- Saturated compounds containing about three to about five carbon atoms are more preferred.
- Triacetin and triethyl citrate are highly preferred. Mixtures are contemplated.
- the penetration enhancer systems of the invention contain the primary or fatty component in combination with one or more of the secondary, or non-fatty, components.
- Preferred enhancement systems will be composed of a fatty acid or ester, eg., linoleic acid, in combination with a glycol, eg., propylene glycol, and, optionally, an ester, eg., triacetin.
- a fatty acid or ester eg., linoleic acid
- glycol eg., propylene glycol
- an ester eg., triacetin.
- the quantities thereof may vary as long as the total quantity of resulting penetrant is beneficial to penetration.
- compositions which exhibit effective bioavailability when applied transmembranally include the bioaffecting and penetration enhancement portions in the following ranges.
- LA Procaterol with Linoleic Acid
- PG Propylene Glycol
- procaterol base through hairless mouse skin was significantly enhanced when a penetration system containing propylene glycol was used.
- Solvent systems containing LA, PG and triethyl citrate (TEC) appear to be highly effective.
- the flux of procaterol base (PB) from four different formulations (F1 to F4) containing linoleic acid, triethyl citrate, and propylene glycol through hairless mouse skin is shown in Table 4.
- the loading capacity of F1 is less than 2%; whereas for F2 to F4 it is more than 2% of PB.
- the solvent system F5 was saturated with procaterol HCl and the flux of procaterol from this formulation was also measured.
- the loading capacity of F5 is about 0.5 percent procaterol HCl.
- Table 5 shows the total amount of drug that permeated through 10 cm2 of hairless mouse skin in the first 24 hours of the experiment and the calculated daily flux values (flux mg/cm2/h 10 cm224 h). The observed differences between actual and calculated values are due to the lag time.
- the concentration of linoleic acid, a representative fatty acid, in propylene glycol was optimized to achieve a maximum permeability coefficient for the cardiotonic compound 4,5-dihydro-6-[4-(IH-imidazole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone.
- the base was prepared as follows; One gram of the hydrochloride of the pyridazinone was dissolved in 10 ml of water to which 3 ml of ammonium hydroxide was added. The precipitate (base) thus formed was extracted with chloroform (2 ⁇ 15 ml). The chloroform solution was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the pyridazinone base was obtained as a solid powder
Abstract
- (a) about 0.2% to about 5% of bioaffecting agent,
- (b) about 1% to about 20% of fatty component, and
- (c) about 80% to about 99% of a secondary component.
Description
- The administration of drugs via oral routes is often associated with a variety of problems, eg., first pass metabolism, gastro-intestinal side effects, unpleasant taste and/or odor, and the like.
- Recent studies have shown that the transdermal administration of drugs offers a viable alternative to oral dosage forms. However, transdermal delivery systems are not always efficacious due to such factors as the failure of the drug to sufficiently penetrate the cutaneous membrane and enter the body to produce therapeutic systemic effects.
- It has been discovered that various drugs can be effectively administered across a body membrane, eg., transdermally, using a novel combination of penetration enhancers.
- These enhancers are generally thought of as solvents for the drug or drugs being used, but it is more accurate to term them penetration enhancers since--via a mechanism which is not clearly understood--they assist in the movement of an active ingredient across a living membrane, eg., the skin, and into the body fluid, eg., the blood stream. The systems which enhance transmembranal penetration are generally combinations of fatty acids and/or their esters.
- The invention relates to compositions and methods for the administration of bioaffecting agents, eg., drugs, via living membranes, eg., skin, via topical application; ie., by contacting the compositions with the living membranes.
- In a preferred embodiment, 0.5-3 wt. % procaterol is combined with 2-90 wt. % linoleic acid and 10-98% propylene glycol to produce compositions useful for transdermal administration.
- Other aspects and advantages will be apparent from the following description of the invention.
- The compositions and methods of the invention have several advantages over the prior art delivery systems. Since the instant system permits delivery via buccal, rectal, mucosal, nasal and dermal membranes, the drug can enter the bloodstream without entering the gastrointestinal tract. Transmembranal dosage forms generally do not produce the side effects, such as nausea and the like, which are often associated with the oral administration of drugs.
- Furthermore, since the instant compositions need not be administered via injection, the unpleasantness of that type of delivery is avoided.
- In general, it has been found that administration via penetration of the drug across a suitable membrane, eg., the cutaneous barrier, is superior to other routes of administration, especially in terms of ease of administration and attainment of sustained release.
- Weight percentages are based on total composition weight unless staged otherwise.
- The bioaffecting agents which can be employed in the compositions of the invention include a wide range of known drug and beneficial substances and/or derivatives thereof.
- By "derivatives thereof" is meant pharmaceutically acceptable derivatives of the bioaffecting base, or drug agent, as well as prodrugs and metablites.
- Using procaterol as an illustration, useful derivatives would include procaterol salts, with the hydrochloride salt being exemplary. Other useful forms of procaterol include procaterol base, procaterol sulfate and the like.
- Mixtures of one or more such forms of a drug, as well as compositions containing a drug in combination with one or more other drugs, are contemplated.
- Depending upon the bioaffecting agent(s) to be employed, a wide range of organic and inorganic salts thereof can be used. The nature of the salt is not essential as long as the drug or other agent maintains its value as a medicament and is compatible with the penetration enhancer(s) or other vehicle(s) employed. Exemplary acid salts include hydrochloride, hydrobromide, orthophosphate , benzoate, maleate, tartarate, succinate, citrate, salicylate, sulfate, acetate, and the like. Useful bioaffecting agents include;
Antihistamines, such as chlorpheniramine maleate, phenimadamine tartarate, pyrilamine maleate, doxylamine succinate, and phenyltolomaxine citrate;
Decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine;
Various alkaloids, such as codeine phosphate, codeine sulfate and morphine;
Laxatives, vitamins and antacids;
Anticholesterolemic and antilipid agents;
Antiarrhythmics such as N-acetylprocainamide;
Antipyretics and analgesics such as acetaminophen, aspirin, and ibuprofen;
Appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; and
Expectorants such as guaifenesin.
- Additional useful active medicaments include anti-inflammatory substances, coronary dilators, cerebral dilators, vasodilators, anti-infectives, psychotropics, antimanics, stimulants, laxatives, decongestants, gastro-intestinal sedatives, antidiarrheal preparations, antianginal drugs, vasodilators, antihypertensive drugs, vasoconstrictors and migraine treatments, antibiotics, tranquilizers, antipsychotics, antitumor drugs, anticoagulants and antithrombotic drugs, hypnotics, sedatives, antiemetics, antinauseants, anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropietic drugs, antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, and the like. Mixtures may be used.
- Preferred drugs for use in the instant compositions and methods are; procaterol, 4,5-dihydro-6-[4-(IH-imidozole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone morphine, hydromorphone, propranolol, chlorpheniramine and derivatives thereof. Procaterol, the pyridazinone, propranolol and their derivatives are most preferred.
- The daily dosages for human use of these preferred drugs are believed to be about 200 mg/day for procaterol and about 2 mg/day. for 45-dihydro-6-[4-(1H-imidazole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone ("the pyridazinone") and higher for propranolol.
- The penetration enhancer systems of the invention contain at least one fatty compound in combination with a non-fatty hydroxyl compound.
- By "fatty" compounds applicants mean compounds related to, or existing as, any of the saturated or unsaturated monocarboxylic acids that occur naturally in the form of glycerides in fats and fatty oils.
- The fatty compounds which can be employed are essential fatty acids, their esters, alcohols and other related compounds. Useful fatty components of the instant enhancement systems include saturated and unsaturated aliphatic compounds. Generally the unsaturated compounds contain about 8 to 24 carbon atoms.
- Fatty acids, alcohols and esters to be employed herein include those containing oleic, linoleic, linoleic, moieties and the like. Mixtures are comtemplated.
- The preferred group of fatty components include linoleic acid (ie., 9,12- octadienoic acid) and related compounds. Suitable esters of this or other fatty acid(s) to be employed include the C 1-3 esters eg., the methyl, ethyl, and propyl esters, and the like.
- When an alcoholic fatty component is employed, it is generally preferred that it contain no more than one hydroxyl group, ie., monohydroxy alcoholic fatty compounds are preferred. One such compound is linoleyl alcohol.
- The use of linoleic acid to enhance the penetration of anti-inflammatory and analgesic agents has been described in Kokai Tokyo Kobo. "Topical Anti-inflammatory and Analgesic Agent" Taisho Pharmaceutics Co., Ltd., Japan, 81, 110, 614 (cl. A61K31/135) Sep tember 1, 1981.
- In addition, several studies have been made on the function of linoleic acid, an essential fatty acid, in skin. Two of these are: C. Prottey, "Investigation of Functions of Essential Fatty Acids in the Skin," British Journal of Dermatology (1977), 97, 29; and E. O. Butcher, "The Penetration of Fat and Fatty Acid into the Skin of the Rat," J. Investig. Dermatol., 1953, 43-48.
- The mechanism by which the linoleic acid or its esters enhances the penetration of the instant combinations is not clearly understood. However, the changes brought about using the instant compositions are systemic and not merely local, ie., at the site where the composition is applied.
- The other, or secondary, component of the penetrant system of the invention is not a fatty substance. Generally, this other component is a solvent for the bioaffecting agent. Useful solvents are generally mono-or polyhydroxyl-containing compounds which may, optionally, contain ester groups.
- Hydroxyl compounds to be used as the secondary component include compounds containing one or more hydroxyl groups. Polyols are preferred. Polyols containing one to four carbon atoms are more preferred. Propylene glycol, polyethylene glycols (eg., PEG 400) and tetraglycols are highly preferred. Isopropanol is also useful. Mixtures are operable.
- The ester group-containing compound useful in the secondary component of the penetration enhancer system will be at least one compound which contains one or more ester groups. Compounds containing 6 to 30 carbon atoms and three or more ester groups are preferred. Saturated compounds containing about three to about five carbon atoms are more preferred. Triacetin and triethyl citrate are highly preferred. Mixtures are contemplated.
- The penetration enhancer systems of the invention contain the primary or fatty component in combination with one or more of the secondary, or non-fatty, components.
- Preferred enhancement systems will be composed of a fatty acid or ester, eg., linoleic acid, in combination with a glycol, eg., propylene glycol, and, optionally, an ester, eg., triacetin.
- When more than one secondary component is used, the quantities thereof may vary as long as the total quantity of resulting penetrant is beneficial to penetration.
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- The following examples illustrate the effectiveness of the penetration enhancers of the invention.
- The experimental method employed to generate the data in the following examples was:
- Skin sections from male hairless mice (5-7 weeks old) were mounted on Franz® diffusion cells with the stratum corneum facing the donor compartment. To remove extraneous debris, the dermal side of the skin was in contact with saline for 2 hours before starting the diffusion experiment. One milliliter of a procaterol solution was placed in the donor compartment which was then occluded with cellophane and Parafilm®. The appearance of Procaterol in the receiver solution (saline) was monitored by withdrawing the entire contents of the receiver chamber at timed intervals. The receiver compartment was then refilled with fresh saline. The samples were filtered through a 0.45 u nylon filter and the drug concentration determined by HPLC. Temperature was maintained at 37°C during the experiment.
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- The loading capacity of F1 is less than 2%; whereas for F2 to F4 it is more than 2% of PB. The solvent system F5 was saturated with procaterol HCl and the flux of procaterol from this formulation was also measured. The loading capacity of F5 is about 0.5 percent procaterol HCl.
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- In this example, the concentration of linoleic acid, a representative fatty acid, in propylene glycol was optimized to achieve a maximum permeability coefficient for the cardiotonic compound 4,5-dihydro-6-[4-(IH-imidazole-1-yl) phenyl]-5-methyl-3-(2H)-pyridazinone.
- The base was prepared as follows; One gram of the hydrochloride of the pyridazinone was dissolved in 10 ml of water to which 3 ml of ammonium hydroxide was added. The precipitate (base) thus formed was extracted with chloroform (2 × 15 ml). The chloroform solution was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the pyridazinone base was obtained as a solid powder
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- The use of excipients and other conventional additives in the components and methods of the invention are contemplated.
- Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT87112412T ATE53301T1 (en) | 1986-08-27 | 1987-08-26 | SYSTEMS FOR IMPROVING PERFORMANCE AND THEIR PREPARATION. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US900865 | 1986-08-27 | ||
US06/900,865 US4908389A (en) | 1986-08-27 | 1986-08-27 | Penetration enhancement system |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0261429A1 true EP0261429A1 (en) | 1988-03-30 |
EP0261429B1 EP0261429B1 (en) | 1990-06-06 |
Family
ID=25413211
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP87112412A Expired - Lifetime EP0261429B1 (en) | 1986-08-27 | 1987-08-26 | Penetration enhancement systems and the preparation thereof |
Country Status (8)
Country | Link |
---|---|
US (1) | US4908389A (en) |
EP (1) | EP0261429B1 (en) |
JP (1) | JPS63126832A (en) |
AT (1) | ATE53301T1 (en) |
CA (1) | CA1316825C (en) |
DE (1) | DE3763011D1 (en) |
ES (1) | ES2036199T3 (en) |
GR (1) | GR3000536T3 (en) |
Cited By (28)
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EP0301589A2 (en) * | 1987-07-31 | 1989-02-01 | Warner-Lambert Company | Procaterol transdermal delivery system |
US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
EP0430491A2 (en) * | 1989-11-17 | 1991-06-05 | Beta Pharmaceuticals Co. | Transdermal delivery device for estradiol and process for manufacturing said device |
US5053227A (en) * | 1989-03-22 | 1991-10-01 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
US5059426A (en) * | 1989-03-22 | 1991-10-22 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
EP0463454A2 (en) * | 1990-06-14 | 1992-01-02 | Dermamed | Transdermal administration to humans and animals |
EP0535237A1 (en) * | 1991-03-20 | 1993-04-07 | Hisamitsu Pharmaceutical Co., Inc. | Composition for relieving skin irritation and external preparation for percutaneous adminstration containing the same |
US5229130A (en) * | 1991-12-20 | 1993-07-20 | Cygnus Therapeutics Systems | Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems |
AU643230B2 (en) * | 1989-08-17 | 1993-11-11 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
US5262165A (en) * | 1992-02-04 | 1993-11-16 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
EP0634179A1 (en) * | 1989-01-11 | 1995-01-18 | Noven Pharmaceuticals, Inc. | Transdermal acrylic multipolymer drug delivery system |
US5445607A (en) * | 1989-10-23 | 1995-08-29 | Theratech, Inc. | Iontophoresis device and method using a rate-controlling electrically sensitive membrane |
US5518734A (en) * | 1991-09-25 | 1996-05-21 | Beta Pharmaceuticals Co. | Transdermal delivery system for estradiol and process for manufacturing said device |
US5705185A (en) * | 1991-09-25 | 1998-01-06 | Beta Pharmaceuticals Co. | Transdermal delivery of estradiol and process for manufacturing said device |
EP0871420A1 (en) * | 1995-04-26 | 1998-10-21 | Theratech, Inc. | Triacetin as a transdermal penetration enhancer |
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US8980309B2 (en) | 2003-10-10 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal testosterone formulation for minimizing skin residues |
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US11103513B2 (en) | 2014-05-22 | 2021-08-31 | TherapeuticsMD | Natural combination hormone replacement formulations and therapies |
US11241445B2 (en) | 2012-12-21 | 2022-02-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
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US5164406A (en) * | 1988-06-02 | 1992-11-17 | Bristol-Myers Squibb Co. | Method for enhancing transdermal penetration and compositions useful therein |
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US5736553A (en) * | 1988-12-15 | 1998-04-07 | Riker Laboratories, Inc. | Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo 4,5-C!quinolin-4-amine |
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- 1987-08-26 JP JP62210362A patent/JPS63126832A/en active Pending
- 1987-08-26 DE DE8787112412T patent/DE3763011D1/en not_active Revoked
- 1987-08-26 ES ES198787112412T patent/ES2036199T3/en not_active Expired - Lifetime
- 1987-08-26 EP EP87112412A patent/EP0261429B1/en not_active Expired - Lifetime
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EP0043738B1 (en) * | 1980-07-09 | 1985-10-02 | THE PROCTER & GAMBLE COMPANY | Penetrating topical pharmaceutical compositions |
EP0095813A2 (en) * | 1982-06-01 | 1983-12-07 | THE PROCTER & GAMBLE COMPANY | Penetrating topical pharmaceutical compositions containing 9-(2-hydroxyethoxymethyl) guanine |
EP0129283A2 (en) * | 1983-06-21 | 1984-12-27 | The Procter & Gamble Company | Improved penetrating topical pharmaceutical compositions containing corticosteroids |
EP0144069A1 (en) * | 1983-12-01 | 1985-06-12 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Highly penetrable medicine for cellular tissue |
Cited By (49)
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EP0301589A3 (en) * | 1987-07-31 | 1989-07-12 | Warner-Lambert Company | Transdermal delivery system |
EP0301589A2 (en) * | 1987-07-31 | 1989-02-01 | Warner-Lambert Company | Procaterol transdermal delivery system |
EP0634179A1 (en) * | 1989-01-11 | 1995-01-18 | Noven Pharmaceuticals, Inc. | Transdermal acrylic multipolymer drug delivery system |
US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
US5053227A (en) * | 1989-03-22 | 1991-10-01 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
US5059426A (en) * | 1989-03-22 | 1991-10-22 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
AU643230B2 (en) * | 1989-08-17 | 1993-11-11 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
US5445607A (en) * | 1989-10-23 | 1995-08-29 | Theratech, Inc. | Iontophoresis device and method using a rate-controlling electrically sensitive membrane |
EP0430491A3 (en) * | 1989-11-17 | 1991-12-27 | Laboratorios Beta S.A. | Transdermal delivery device for estradiol and process for manufacturing said device |
EP0430491B1 (en) * | 1989-11-17 | 1994-06-08 | Beta Pharmaceuticals Co. | Transdermal delivery device for estradiol and process for manufacturing said device |
EP0430491A2 (en) * | 1989-11-17 | 1991-06-05 | Beta Pharmaceuticals Co. | Transdermal delivery device for estradiol and process for manufacturing said device |
EP0463454A3 (en) * | 1990-06-14 | 1992-06-10 | Dermamed | Transdermal administration to humans and animals |
EP0463454A2 (en) * | 1990-06-14 | 1992-01-02 | Dermamed | Transdermal administration to humans and animals |
EP0535237A4 (en) * | 1991-03-20 | 1993-09-15 | Hisamitsu Pharmaceutical Co. Inc. | Composition for relieving skin irritation and external preparation for percutaneous adminstration containing the same |
EP0535237A1 (en) * | 1991-03-20 | 1993-04-07 | Hisamitsu Pharmaceutical Co., Inc. | Composition for relieving skin irritation and external preparation for percutaneous adminstration containing the same |
US5705185A (en) * | 1991-09-25 | 1998-01-06 | Beta Pharmaceuticals Co. | Transdermal delivery of estradiol and process for manufacturing said device |
US5518734A (en) * | 1991-09-25 | 1996-05-21 | Beta Pharmaceuticals Co. | Transdermal delivery system for estradiol and process for manufacturing said device |
US5229130A (en) * | 1991-12-20 | 1993-07-20 | Cygnus Therapeutics Systems | Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems |
US5262165A (en) * | 1992-02-04 | 1993-11-16 | Schering Corporation | Transdermal nitroglycerin patch with penetration enhancers |
EP0871420A1 (en) * | 1995-04-26 | 1998-10-21 | Theratech, Inc. | Triacetin as a transdermal penetration enhancer |
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Also Published As
Publication number | Publication date |
---|---|
CA1316825C (en) | 1993-04-27 |
ATE53301T1 (en) | 1990-06-15 |
ES2036199T3 (en) | 1993-05-16 |
US4908389A (en) | 1990-03-13 |
JPS63126832A (en) | 1988-05-30 |
EP0261429B1 (en) | 1990-06-06 |
GR3000536T3 (en) | 1991-07-31 |
DE3763011D1 (en) | 1990-07-12 |
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